Why the study?
Measuring GLP-1 in rodent plasma is difficult due to rapid degradation by DPP-4 and neprilysin, prompting investigation into whether dual inhibition enables measurement of intact GLP-1 secretion in rats.
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Population
Male rats
Comparison
Inhibition with sacubitril and sitagliptin vs control
Design
In vivo animal experimental study
Enables reliable GLP-1 measurement in mice via DPP-4/neprilysin inhibition; leaves open broader rodent or clinical applicability.
Measuring glucagon-like peptide-1 (GLP-1) in plasma from rodents is difficult since the active peptide GLP-1(7-36)NH2 is rapidly degraded into the inactive GLP-1(9-36)NH2 by the enzyme dipeptidyl peptidase 4 (DPP-4). Additionally, the endopeptidase neprilysin (NEP24.11) further degrades both forms of GLP-1. In mice, in vivo inhibition of DPP-4, preferably combined with inhibition of neprilysin, enables measurement of GLP-1 secretion in plasma. We investigated whether the same inhibitions enable measurement of GLP-1 secretion in rats based on quantification of intact GLP-1. To investigate in vivo degradation of exogenous GLP-1, the neprilysin inhibitor (sacubitril 0.3 mg/kg) and the DPP-4 inhibitor (sitagliptin 10 mg/kg) were injected intravenously 15 minutes before IV administration of GLP-1(7-36)NH2 (2 pmol). For endogenous GLP-1, sacubitril and sitagliptin were administered orally to 7-hours fasted rats 60 minutes prior to oral glucose administration (2 g/kg). In both experiments blood was collected, and intact GLP-1 plasma concentrations were measured. The inhibitors stabilized exogenous GLP-1 and resulted in a 13-fold higher net area under the curve of intact GLP-1 plasma concentrations (509.3 ± 70.62 vs 39.0 ± 21.65 pmol/L*min). The peak of intact GLP-1 concentrations in response to oral glucose was 7-fold higher in inhibitor-treated rats compared to control rats, in which the GLP-1 response was barely detectable. Thus, in vivo inhibition of both DPP-4 and neprilysin activity stabilized newly secreted GLP-1, thereby enabling estimation of GLP-1 secretion in rats, which is otherwise notoriously difficult due to rapid degradation.
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Galsgaard et al. (2025) studied this question.
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